JP5297815B2 - Pharmaceutical composition - Google Patents

Abstract

To provide a pharmaceutical composition which can enhance the storage stability of 1-(1-hydroxymethyl-2,3-dihydroxypropyloxymethyl)-2-nitroimidazole without impairing the effect of the compound. The pharmaceutical composition includes 1-(1-hydroxymethyl-2,3-dihydroxypropyloxymethyl)-2-nitroimidazole, which is represented by formula (1) : and a compound having chelating ability.

Description

  The present invention relates to pharmaceutical compositions, and more particularly to pharmaceutical compositions useful for cancer radiotherapy.

  2-Nitroimidazole derivatives are already known to be useful drugs that have radioresistance in cancer radiotherapy, increase the radiosensitivity of cancer cells in hypoxia, and increase the effect of radiotherapy. Among 2-nitroimidazole derivatives, in particular, 1- (1-hydroxymethyl-2,3-dihydroxypropyloxymethyl) -2-nitroimidazole represented by the following general formula (1) has high hydrophilicity and is a nerve. Since there is almost no migration to cells, it is a radiosensitizer without central toxicity (see, for example, Patent Documents 1 to 3). Further, in the compound (1), in addition to the radiosensitizing effect on hypoxic cells, nucleic acid hydroxide scavenging action (see, for example, Patent Document 4) and apoptosis / signal retention action (for example, Patent Document 5). And the like, and can be said to be useful drugs for cancer treatment.

  In general, it is said that the mechanism of action of 2-nitroimidazole derivatives is due to reoxygenation derived from the very strong electron affinity of the nitro group at the 2-position. It also means the instability of this group, and this group has the property of being easily decomposed to generate nitric oxide and the like. It is also known that side chain cleavage occurs under acidic conditions and 2-nitroimidazole is liberated. That is, in the 2-nitroimidazole derivative, it can be said that the stability of the compound is threatened by the nitro group at the 2-position, which is an effective group. Therefore, it has been desired to develop a means for improving the stability during storage without impairing the effect of the 2-nitroimidazole derivative.

On the other hand, as a means for stabilizing a compound having a nitro group, stabilization with a phospholipid (for example, see Patent Document 6), stabilization with a buffer such as citric acid-citrate, phosphoric acid-phosphate, etc. (For example, refer to Patent Document 7). It is also known that chelating agents make a favorable contribution to the stability of nitro compounds (see, for example, Patent Document 6). However, the means for stabilizing the 2-nitroimidazole derivative is not known, and how the chelating agent contributes to the stabilization of the 2-nitroimidazole derivative has not been known at all.
JP-A-3-223258 WO1994 / 014778 JP 2003-321459 A JP 2005-27515 A JP 09-77667 A Japanese translation of PCT publication No. 2003-512430 Japanese Unexamined Patent Publication No. 07-1226017

  The present invention has been made under such circumstances, and stability during storage without impairing the effects of 1- (1-hydroxymethyl-2,3-dihydroxypropyloxymethyl) -2-nitroimidazole. It is an object of the present invention to provide a pharmaceutical composition capable of improving the quality.

  In view of such a situation, as a result of intensive research efforts, the present inventors have obtained a compound having a chelating ability to 1- (1-hydroxymethyl-2,3-dihydroxypropyloxymethyl) -2-nitroimidazole. If blended, the ability of 1- (1-hydroxymethyl-2,3-dihydroxypropyloxymethyl) -2-nitroimidazole to be maintained while the decomposition of 2-nitro group and the release of 2-nitroimidazole can be prevented. The present invention has been completed.

  That is, the present invention provides the following general formula (1)

A pharmaceutical composition containing 1- (1-hydroxymethyl-2,3-dihydroxypropyloxymethyl) -2-nitroimidazole represented by the formula (1) and a compound having a chelating ability is provided.
The present invention also provides use of the above composition for producing a radiosensitizer.
The present invention also provides cancer radiotherapy characterized by administering an effective amount of the above composition and irradiating with radiation.

  According to the present invention, the stability during storage can be improved without impairing the effect of 1- (1-hydroxymethyl-2,3-dihydroxypropyloxymethyl) -2-nitroimidazole, which is effective. High-quality cancer radiotherapy is possible.

FIG. 4 is a diagram showing the results of a severe test of Example 1. It is a figure which shows the result of the severe test of Example 2. It is a figure which shows the result of the severe test of Example 3. It is a figure which shows the result of the severe test of Example 4. It is a figure which shows the result of the severe test of Example 5. It is a figure which shows the result of the severe test of Example 6. It is a figure which shows the result of the severe test of Example 7. It is a figure which shows the result of the severe test of Example 8. It is a figure which shows the result of the severe test of Example 9. It is a figure which shows the result of the severe test of the comparative example 1. It is a figure which shows the radiosensitization effect of each pharmaceutical composition.

  The 1- (1-hydroxymethyl-2,3-dihydroxypropyloxymethyl) -2-nitroimidazole (compound (1)) used in the present invention has four steric forms: RS, SR, RR, and SS. There are isomers. In the present invention, these optically active substances may be used, or a mixture such as a racemate in which the optically active substance is mixed may be used. Particularly preferred from the standpoint of effectiveness are isomers of the stereostructure represented by the following general formula (2), and SR and RS racemates of the isomer of the stereostructure represented by the general formula (3). Is the body.

  In clinical trials, the compound (1) is stored at 5 ° C. for the purpose of ensuring stability. Since such storage conditions are attached, it is difficult to handle the compound (1). Exist. Compound (1) can be produced according to the method described in Patent Document 1 or Patent Document 2, such as 2-nitro-1-trimethylsilylimidazole and 2-acetoxymethoxy-1,3,4-triacetoxybutane. Can be condensed in the presence of Lewis acid, and then reacted with sodium methoxide or the like for deacetylation. At this time, the steric properties of 2-acetoxymethoxy-1,3,4-triacetoxybutane are also observed in the final product 1- (1-hydroxymethyl-2,3-dihydroxypropyloxymethyl) -2-nitroimidazole. Reflected.

  In the pharmaceutical composition of the present invention, the content of the compound (1) is preferably 1 to 10% by mass, more preferably 2 to 8% by mass. If the content of compound (1) is too small, it will not be possible to contain a sufficient amount of 1- (1-hydroxymethyl-2,3-dihydroxypropyloxymethyl) -2-nitroimidazole in the pharmaceutical preparation. If the effect of (1) is difficult to be exhibited and the other is too much, the vehicle may not be completely dissolved, so that the stability is lacking.

The compound having chelating ability used in the present invention is not particularly limited as long as it can be used as an additive for pharmaceuticals. For example, aldonic acids such as gluconic acid and glucoceptic acid, aldaric acids such as tartaric acid and glucaric acid, Gururonic acid and other uronic acids, ascorbic acid and other sugar acids or salts thereof; edetic acid and pentetic acid and other aminopolycarboxylic acids or salts thereof; citric acid and other oxycarboxylic acids or salts thereof; diethylamine and other amines Compounds; polyoxyethylene castor oils such as polyoxyl 35 castor oil; Of these, sugar acids or salts thereof, aminopolycarboxylic acids or salts thereof, and amine compounds are preferable, and tartaric acid or salts thereof, ascorbic acid or salts thereof, pentetic acid or salts thereof, and diethylamine are particularly preferable.
Examples of the salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; organic amine salts such as ammonium salt, triethylamine salt, triethanolamine salt and monoethanolamine salt Preferred examples include basic amino acid salts such as lysine salts and alginates. A compound having a chelating ability can contain only one species, or a combination of two or more species.

In the pharmaceutical composition of the present invention, the content of the compound having a chelating ability is preferably 0.005 to 5% by mass, more preferably 0.01 to 2% by mass. If the content of the compound having a chelating ability is too small, there may be cases where the effect of improving the stability is not achieved. On the other hand, if the content is too large, the contribution to stability reaches its peak, and the degree of freedom of formulation may be inhibited.
Specifically, when sugar acid or a salt thereof is used, it is preferably 0.01 to 2% by mass, more preferably 0.025 to 1.1% by mass; edetic acid or a salt thereof or pentetic acid, When an aminopolycarboxylic acid such as trisodium calcium pentetate or a salt thereof is used, it is preferably 0.01 to 2% by mass, more preferably 0.01 to 1.0% by mass, especially pentasodium pentetate. In the case, it is preferably 0.01 to 0.8% by mass, more preferably 0.01 to 0.5% by mass; when oxycarboxylic acid or a salt thereof is used, preferably 0.01 to 2% by mass. %, More preferably 0.02 to 1% by mass; when an amine compound is used, preferably 0.01 to 0.1% by mass, more preferably 0.01 to 0.08% by mass; polyoxyethylene When using the Nhimashi oils, preferably 0.01 to 0.8 wt%, more preferably 0.01 to 0.5 wt%.

  The pharmaceutical composition of the present invention is preferably used for the purpose of increasing the sensitivity of hypoxic cancer cells to radiation in medicine, particularly in the treatment of cancer, particularly in cancer treatment by radiation. Suitable examples of cancer include lung cancer and pancreatic cancer. Specifically, cancer radiotherapy may be performed by administering the composition of the present invention and irradiating with radiation.

  The dosage form of the pharmaceutical composition is not particularly limited and can be appropriately selected depending on the therapeutic purpose. For example, oral dosage formulations such as tablets, capsules, granules, film coating agents, powders, syrups; injections, suppositories, Examples include parenteral administration such as inhalants, transdermal absorption agents, eye drops, nasal drops, and the like, and injectable preparations are particularly preferred because of rapid metabolism. Injectable preparations include preparations for infusion administration and are preferably infusion administration preparations. This is because the dosage of 1- (1-hydroxymethyl-2,3-dihydroxypropyloxymethyl) -2-nitroimidazole, which is an active ingredient, is large, so that the necessary amount of the preparation increases, and there is a danger in temporary administration. This is because there are cases. Such an injection preparation is not particularly limited in either a solution form or a freeze-dried form, but is preferably a solution form from the viewpoint of obtaining stable solubility. Preferred examples of the vehicle in the form of a solution include pure water, physiological saline, and a glucose solution that may be isotonic.

The pharmaceutical composition of the present invention can contain any formulation components that are usually used in pharmaceutical preparations, as long as the effects of the present invention are not impaired. Examples of such optional components include polyhydric alcohols such as macrogol; isotonic agents such as sodium chloride; buffer salts such as phosphates; excipients such as crystalline cellulose and starch; Nonionic surfactants such as polyoxyethylene hydrogenated castor oil; anionic surfactants such as sodium lauryl sulfate; thickening polysaccharides such as gum arabic; lubricants such as magnesium stearate; colorants; Flavoring agents; binders such as hydroxypropylcellulose; coating agents such as “Eudragit” (registered trademark), and the like. In the case of an injection preparation in the form of a solution, a particularly preferred form is a form containing only a compound having chelating ability with the compound (1) and a vehicle and not containing other components.
The pharmaceutical composition of this invention can be manufactured by processing the said essential component and arbitrary components by a conventional method.

  The dosage of the pharmaceutical composition of the present invention can be appropriately selected in consideration of the patient's body weight, age, sex, symptoms, etc. In the case of normal adults, 1- (1-hydroxymethyl-2,3-dihydroxypropyloxy) Preferably, 1-10 g of methyl) -2-nitroimidazole is administered per day.

  Hereinafter, the present invention will be described in more detail with reference to examples, but it goes without saying that the present invention is not limited to such examples.

Example 1
Injectable solutions (drug compositions 1 to 6) for infusion administration, which are pharmaceutical compositions of the present invention, were prepared according to the formulation shown below. That is, the formulation components were weighed into a container and dissolved by stirring. Each preparation is stored for 9 or 10 days under severe conditions at 55 ° C., and the content of 1- (1-hydroxymethyl-2,3-dihydroxypropyloxymethyl) -2-nitroimidazole is periodically determined. It was. As a control, a 5% by mass aqueous solution of the compound (1) was used. The results are shown in FIG.
As can be seen from FIG. 1, in the pharmaceutical composition of the present invention, 1- (1-hydroxymethyl-2,3-dihydroxypropyloxymethyl) -2-nitroimidazole can exist stably even under severe conditions.

Example 2
In the same manner as in Example 1, injectable solutions for infusion administration (pharmaceutical compositions 7 to 10), which are pharmaceutical compositions of the present invention, were prepared according to the following formulation. Each formulation was stored under severe conditions at 55 ° C. for 8 days, and the content of 1- (1-hydroxymethyl-2,3-dihydroxypropyloxymethyl) -2-nitroimidazole was quantified periodically. As a control, a 5% by mass aqueous solution of the compound (1) was used. The results are shown in FIG.
As can be seen from FIG. 2, in the pharmaceutical composition of the present invention, 1- (1-hydroxymethyl-2,3-dihydroxypropyloxymethyl) -2-nitroimidazole can be stably present even under severe conditions.

Example 3
In the same manner as in Example 1, injectable solutions for infusion administration (pharmaceutical compositions 11 to 14), which are pharmaceutical compositions of the present invention, were prepared according to the following formulation. Each formulation was stored under severe conditions at 55 ° C. for 8 days, and the content of 1- (1-hydroxymethyl-2,3-dihydroxypropyloxymethyl) -2-nitroimidazole was quantified periodically. As a control, a 5% by mass aqueous solution of the compound (1) was used. The results are shown in FIG.
As can be seen from FIG. 3, in the pharmaceutical composition of the present invention, 1- (1-hydroxymethyl-2,3-dihydroxypropyloxymethyl) -2-nitroimidazole can be stably present even under severe conditions. .

Example 4
In the same manner as in Example 1, injectable solutions for infusion administration (pharmaceutical compositions 15 to 17), which are pharmaceutical compositions of the present invention, were prepared according to the following formulation. Each formulation was stored under severe conditions at 55 ° C. for 8 days, and the content of 1- (1-hydroxymethyl-2,3-dihydroxypropyloxymethyl) -2-nitroimidazole was quantified periodically. As a control, a 5% by mass aqueous solution of the compound (1) was used. The results are shown in FIG.
As can be seen from FIG. 4, in the pharmaceutical composition of the present invention, 1- (1-hydroxymethyl-2,3-dihydroxypropyloxymethyl) -2-nitroimidazole can be stably present even under severe conditions.

Example 5
In the same manner as in Example 1, injectable solutions for infusion administration (pharmaceutical compositions 18 to 21), which are pharmaceutical compositions of the present invention, were prepared according to the following formulation. Each formulation was stored under severe conditions at 55 ° C. for 8 days, and the content of 1- (1-hydroxymethyl-2,3-dihydroxypropyloxymethyl) -2-nitroimidazole was quantified periodically. As a control, a 5% by mass aqueous solution of the compound (1) was used. The results are shown in FIG.
As is apparent from the results of FIG. 5, in the pharmaceutical composition of the present invention, 1- (1-hydroxymethyl-2,3-dihydroxypropyloxymethyl) -2-nitroimidazole can exist stably even under severe conditions. Recognize.

Example 6
In the same manner as in Example 1, injectable solutions for infusion administration (pharmaceutical compositions 22 to 24), which are pharmaceutical compositions of the present invention, were prepared according to the following formulation. Each formulation was stored under severe conditions at 55 ° C. for 8 days, and the content of 1- (1-hydroxymethyl-2,3-dihydroxypropyloxymethyl) -2-nitroimidazole was quantified periodically. As a control, a 5% by mass aqueous solution of the compound (1) was used. The results are shown in FIG.
As can be seen from FIG. 6, in the pharmaceutical composition of the present invention, 1- (1-hydroxymethyl-2,3-dihydroxypropyloxymethyl) -2-nitroimidazole can exist stably even under severe conditions.

Example 7
In the same manner as in Example 1, injectable solutions for infusion administration (pharmaceutical compositions 25 to 28), which are pharmaceutical compositions of the present invention, were prepared according to the following formulation. Each formulation was stored under severe conditions at 55 ° C. for 8 days, and the content of 1- (1-hydroxymethyl-2,3-dihydroxypropyloxymethyl) -2-nitroimidazole was quantified periodically. As a control, a 5% by mass aqueous solution of the compound (1) was used. The results are shown in FIG.
As can be seen from FIG. 7, in the pharmaceutical composition of the present invention, 1- (1-hydroxymethyl-2,3-dihydroxypropyloxymethyl) -2-nitroimidazole can be stably present even under severe conditions.

Example 8
In the same manner as in Example 1, injectable solutions for infusion administration (pharmaceutical compositions 29 to 32), which are pharmaceutical compositions of the present invention, were prepared according to the following formulation. Each formulation was stored under severe conditions at 55 ° C. for 8 days, and the content of 1- (1-hydroxymethyl-2,3-dihydroxypropyloxymethyl) -2-nitroimidazole was quantified periodically. As a control, a 5% by mass aqueous solution of the compound (1) was used. The results are shown in FIG.
As can be seen from FIG. 8, in the pharmaceutical composition of the present invention, 1- (1-hydroxymethyl-2,3-dihydroxypropyloxymethyl) -2-nitroimidazole can exist stably even under severe conditions.

Example 9
In the same manner as in Example 1, injectable solutions for infusion administration (pharmaceutical compositions 33 to 36), which are pharmaceutical compositions of the present invention, were prepared according to the following formulation. Each formulation was stored under severe conditions at 55 ° C. for 8 days, and the content of 1- (1-hydroxymethyl-2,3-dihydroxypropyloxymethyl) -2-nitroimidazole was quantified periodically. As a control, a 5% by mass aqueous solution of the compound (1) was used. The results are shown in FIG.
As can be seen from FIG. 9, in the pharmaceutical composition of the present invention, 1- (1-hydroxymethyl-2,3-dihydroxypropyloxymethyl) -2-nitroimidazole can be stably present even under severe conditions.

Comparative Example 1
An injectable preparation for infusion administration was prepared in the same manner as in Example 1 except that a phosphate having only a buffering action was used instead of the compound having chelating ability. As a control, a 5% by mass aqueous solution of the compound (1) was used. FIG. 10 shows the results of a storage test of the preparation under severe conditions at 55 ° C. for 10 days.
As is clear from FIG. 10, the composition containing the phosphate had a compound (1) content of less than 95% by mass on the 9th day, confirming the effect of the compound having chelating ability. From this, it can be seen that the effect of the pharmaceutical composition of the present invention is not the effect of the buffer salt but the chelating action.

Test example 1
The radiosensitizing effect was examined by the Micronucleus method using mouse squamous cell carcinoma cell SCCVII.
The mouse squamous cell carcinoma cell SCCVII was aerated with 95% N ₂ + 5% CO ₂ for 20 minutes to hypoxia, and then X-rays (0, 1, 2, 3 Gy) were present in the presence of PBS and the following preparation. Irradiated. The preparations were the pharmaceutical composition 10 of Example 2, the pharmaceutical composition 12 of Example 3, the pharmaceutical composition 15 of Example 4, the pharmaceutical composition 21 of Example 5, the pharmaceutical composition 23 of Example 6, and the Example 7. The pharmaceutical composition 28 of Example 8, the pharmaceutical composition 32 of Example 8, and the pharmaceutical composition 36 of Example 9, and a 5% by mass aqueous solution of Compound (1) (racemic) as a control. After irradiation, the cells were washed and cultured in the presence of cytochalasin B for about 24 hours to form binuclear cells. This was fixed and fluorescently stained, and the number of binuclear cells and the number of micronuclei were counted to determine the frequency of micronucleus generation. The results are shown in FIG.
In FIG. 11, A is a control, D is a pharmaceutical composition 15, I is a pharmaceutical composition 23, M is a pharmaceutical composition 28, N is a pharmaceutical composition 12, O is a pharmaceutical composition 10, and T Represents a pharmaceutical composition 21, U represents a pharmaceutical composition 32, and V represents a pharmaceutical composition 36. For PBS and any of the preparations, no change was observed in the frequency of micronuclei in the non-irradiated group, and no direct effect on the cells was observed. That is, no direct toxicity to cells due to the addition of an additive was observed. Moreover, in the irradiation group, the hypoxic radiosensitization effect was recognized by any formulation. In particular, with respect to the pharmaceutical composition 10, the pharmaceutical composition 12, the pharmaceutical composition 15, the pharmaceutical composition 23, and the pharmaceutical composition 28, the sensitizing effect is changed as compared with the control in which no compound having chelating ability is added. I understand that there is no.

Claims (5)

The following general formula (1)

1- (1-hydroxymethyl-2,3-dihydroxypropyloxymethyl) -2-nitroimidazole and a compound having a chelating ability represented by:
The compound having the chelating ability is a sugar acid or a salt thereof, an aminopolycarboxylic acid or a salt thereof (0.01 to 0.1% by mass in the case of pentetate pentasodium), an oxycarboxylic acid or a salt thereof, A radiation sensitizer that is one or more selected from 0.01 to 0.05% by mass of diethylamine and 0.05 to 1.0% by mass of polyoxyethylene castor oil . The radiation sensitizer according to claim 1 , wherein the sugar acid salt is an alkaline earth metal salt of gluconic acid, glucoceptic acid, tartaric acid, glucuronic acid, glucaric acid or ascorbic acid. The compound represented by the general formula (1) is an isomer having a stereostructure represented by the following general formula (2) and an RS · SR racemic isomer having a stereostructure represented by the general formula (3). radiosensitizer according to claim 1 or 2 which is the body.

The radiosensitizer according to any one of claims 1 to 3 , which is an injection. The radiosensitizer of any one of Claims 1-4 whose content of the compound represented by the said General formula (1) is 1-10 mass%.

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